This is a renewal application of two years of the R01 grant funded by NIH American Recovery Reinvestment Act (ARRA). This grant had been funded from July 15, 2009 to June 30, 2011 and has led to a series of fundamental principles concerning the role of Interleukin 15 (IL-15) in EE pathogenesis. This renewal application seeks to extend our basic and translational analysis of EE, aimed at providing the role of IL-15 and IL-15 responsive cells in the regulation of esophageal eosinophilia in human EE. In the first cycle of the two- year R01 grant funding, we identified several key molecules that are responsible for the initiation and progression of EE pathogenesis in experimental models and have developed evidence that these findings apply to human EE. The details of our findings are presented in the progress report. In brief, we have demonstrated that induced mRNA/protein of IL-15 and iNKT cells in the esophageal biopsies of humans EE and provided evidence that IL-15 and iNKT cells have a critical role in the initiation and progression of aeroallergen or food allergen (peanut)-induced experimental EE. IL-15 has been identified as an important player in allergic immune responses; it mediates diverse biological responses, ranging from proliferation and differentiation. Antigen presenting cell-derived IL15 stimulates the proliferation of naive and CD8+ T cells, iNKT cells and enhances the differentiation of naive T cells towards a Th2 phenotype in the presence of IL4. Additionally, we present preliminary data that it activates B cells and induces IgE. Therefore, in the extended cycle of grant tenure, we propose to test the central hypothesis that chronic IL-15 expression leads to the development of IgE-associated EE pathogenesis and that the surface molecules of IL-15, IL-15-responsive cells, chemokines, and mediators are the potential diagnostic and therapeutic target molecules for human EE. The three specific aims will test our central hypothesis. In the first aim, we will test several sub-hypotheses by examining esophageal transcript profile of IL-15 overexpressed mice, role of IL-15 in the induction of mast cells and B cell growth, activation, and proliferation and the mechanism of Ig class switching in EE. A correlation of IL-15 will also be examined for the development of esophageal furrows, rings, and stricture in human EE. The second aim will test the hypothesis that IL-15 and the cell surface molecules and chemokines of IL-15-responsive cells may be novel diagnostic biomarkers for human EE. We will test several related sub-hypotheses concerning the mRNA and protein levels of IL-15, IL-15R, IgE, CD1d, V24, and chemokines CXCL16 in the blood of normal individuals, gastroesophageal reflux disease (GERD) and EE patients. In the third aim, we propose a set of experiments designed to test several related primary hypotheses focused around iNKT cells and IL-15 being novel target molecules for EE therapy. Our studies are timely given the recent attention that EE is receiving in the medical community.